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Background: Oral opioid analgesics have been used for management of peri- and postoperative analgesia in patients undergoing axillary dissection. The axillary region is a difficult zone to block and does not have a specific regional anesthesia technique published that offers its adequate blockade., Methods: After institutional review board approval, anatomic and radiological studies were conducted to determine the deposition and spread of methylene blue and local anesthetic injected respectively into the axilla via the thoracic inter-fascial plane. Magnetic Resonance Imaging studies were then conducted in 15 of 34 patients scheduled for unilateral breast surgery that entailed any of the following: axillary clearance, sentinel node biopsy, axillary node biopsy, or supernumerary breasts, to ascertain the deposition and time course of spread of solution within the thoracic interfascial plane in vivo., Results: Radiological and cadaveric studies showed that the injection of local anesthetic and methylene blue via the thoracic inter-fascial plane, using ultrasound guide technique, results in reliable deposition into the axilla. In patients, the injection of the local anesthetic produced a reliable axillary sensory block. This finding was supported by Magnetic Resonance Imaging studies that showed hyper-intense signals in the axillary region., Conclusions: These findings define the anatomic characteristics of the thoracic interfascial plane nerve block in the axillary region, and underline the clinical potential of this novel nerve block., (Copyright © 2016 Sociedade Brasileira de Anestesiologia. Publicado por Elsevier Editora Ltda. All rights reserved.)

The title carbene (4) was generated as a highly reactive species in solution by photoirradiation of 10-diazobicyclo[6.3.0]undecapentaene (5) using a high-pressure mercury lamp. Carbene 4 reacts with benzene to afford two isomeric adducts, 10-phenylbicyclo[6.3.0]undecapentaene (10) and tricyclo[9.3.0 3, 10 .0]heptadeca-1,3(10),4,6,8,12,14,16-octaene (11). The reactivity toward benzene is a characteristic of an electrophilic aromatic carbene analogous to cyclopentadienylidene 1. In contrast, the reaction of 4 with methanol produces 7-methoxybicyclo[6.3.0]undeca-1,3,5,8,10-pentaene (15). When [D 1 ]methanol was employed as a reactant, the 10-deuterated analogue was formed. The results clearly indicate the formation of bicyclo[6.3.0]undecapentaenyl cation (7) as a novel 10 π-electronic compound by protonation of 4. Theoretical calculations indicate that the 2- and 7-positions of the cation have the largest positive charge in the cation. Moreover, the carbene was generated in the presence of tert-butyl hydroperoxide in aqueous tetrahydrofuran to afford azulene through oxidation of 7, followed by decarbonylation. The nucleophilic property of carbene 3 is similar to that of cycloheptatrienylidene 2. Thus, 4 can be regarded as a novel ambiphilic aromatic carbene., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Hypothermic machine perfusion (HMP) has a potential to relieve the current donor liver crisis by providing an improved and extended preservation method. This study examined the effect of HMP on hepatocellular functions, using a prototype liver transporter capable of preserving livers for 24 hours. Livers obtained from adult farm pigs (28 to 32 kg body weight) were divided into three groups: fresh control, HMP, and simple cold storage (n = 4 each). A 4-hour normothermic reperfusion of livers was conducted to assess hepato-metabolic and cellular functions. The hepatic transport function, as indicated by canalicular excretion of indocyanine green, was improved in the HMP group than in the SCS group. The overall tissue viability, as indicated by oxygen consumption levels, was notably improved in HMP and control livers as compared to the SCS group. Higher bile production in both the preserved groups as compared to the fresh control livers could be a result of biliary edema and leakage of plasma into the canaliculus. The hepato-cellular injury, measured by ALT, release was significantly greater in the SCS group as compared to the HMP and control groups. These findings suggest that HMP could be a better method to preserve hepatic function and overall tissue viability as compared to SCS. Improved hepatic functions are indirect indicators of superior microcirculation and sinusoidal endothelial cell functions. Further studies in progress will evaluate these functions to confirm the significance of these observations.

Liver transplantation is often the only effective treatment for end stage liver diseases resulting from cirrhosis, hepatitis, progressive jaundice, and biliary atresia. Hypothermic machine perfusion (HMP) preservation may enhance donor pool by extending preservation time and reclaiming marginal donor livers including those from non-heart beating donors (NHBD), as demonstrated in the kidney. However, current HMP protocols have not been successful in improving extended preservation of livers and the major cause of preservation injury remains unknown. An intravital microscopy study was conducted to understand the flow dynamics of sinusoidal perfusion during 24h HMP with cold modified University of Wisconsin (UW) solution. Fluorescein isothiocynate (FITC) labeled albumin was utilized to visualize microvascular space and FITC labeled red blood cells (RBCs) were used to visualize flow dynamics during HMP. A heterogeneous flow pattern with regions of red cell stasis was observed after 24-h HMP. To examine the cause of red cell stasis, intravital and confocal microscopy studies of endothelial cells (ECs) structure labeled with DiI acetylated low-density lipoprotein (DiI acLDL) were conducted. These studies suggest that morphological changes in EC structures occurred during 24h HMP, which may cause obstruction to the sinusoidal flow. Histological findings confirm these results. As a result, heterogeneous flow pattern, red cell stasis, and edema occur, which may lead to the failure of these tissues following extended HMP.

Background: Non-heart-beating donor (NHBD) livers are an untapped source with the potential to provide relief to the current donor shortage problem. Hypothermic machine perfusion (MP) has the potential to reclaim and preserve these marginal donor organs., Methods: This study compared 5-day survival in a rat NHBD liver transplantation model with simple cold storage (SCS) and MP-preserved tissues that had experienced 30 min of warm ischemia followed by a 5-hr preservation period with the University of Wisconsin solution. Total release of lactate dehydrogenase (LDH) and alanine aminotransferase (ALT) were determined at major time points. Bilirubin levels and histology were examined after 5-day survival., Results: Six of seven control livers and five of six MP livers survived, whereas SCS tissues had survival in zero of seven. The results showed that MP livers had reduced release of LDH and ALT after 5 hr of storage, 5.07+/-1.42 and 2.02+/-0.69 U (mean+/-SE), respectively, compared with SCS, 15.54+/-0.81 and 3.41.3+/-0.73 U, respectively. Bilirubin values after 5-day survival of MP livers (1.17+/-0.49 mg/dL) were comparable to controls (0.91+/-0.36 mg/dL). Histology confirms that SCS displayed increased necrosis and MP tissue showed regions of near normal hepatic structure., Conclusions: These results suggest that MP for 5 hr improves survival and reduces cellular damage of liver tissue that has experienced 30 min of warm ischemia when compared with SCS tissues. Further studies need to be conducted, but this study suggests that MP preservation has the potential to reclaim and preserve NHBD liver tissues.

Background: Hypothermic machine perfusion preservation has the potential to relieve the current donor shortage problem by reclaiming and preserving marginal donor organs including those from viable non-heart-beating donors. A number of problems exist with the current machine perfusion technology for preserving livers, and much research is needed to determine the clinical impact of this technology in preserving non-heart-beating donor livers., Methods: This study was conducted to compare the poststorage function and microcirculation of simple cold stored and machine perfusion preserved livers that had experienced 30 min of warm ischemia followed by a 10 hr preservation period. In an isolated rat liver perfusion model, lactate dehydrogenase activity, indocyanine green secretion, and portal pressure values were determined at major time points. An intravital microscopy was conducted to assess microcirculation., Results: The results showed an increase in flow homogeneity of machine perfused livers, which correlated with the reduction in portal pressure when compared with simple cold storage (5.4+/-0.4 vs. 8.7+/-0.6 mm Hg). A reduction in lactate dehydrogenase levels in the perfusate (333+/-22 vs.103+/-8 U/L) and an increase in bile production of the machine perfused livers (4.9+/-0.5 vs. 33.2+/-1.7 microg/min/g liver) and indocyanine green secretion (11.7+/-1.7 vs. 21.2+/-2.1 Abs/g bile) were observed at all time points (mean+/-SE of final point given). Intravital microscopic examination indicated that large regions of non flow, as indicated by the absence of fluorescein isothiocyanate-labeled albumin, were observed in the simple cold stored tissue, whereas machine perfused liver showed increase flow homogeneity. Values of bile production, indocyanine secretion, and cellular damages were comparable with controls. Histologic examination confirmed that simple cold stored tissue displayed increased vacuolization, and machine perfused tissue showed regions of normal hepatic structure., Conclusion: These results suggest that machine perfusion for 10 hr improves both poststorage function and microcirculation while reducing cellular damage of liver tissue that has experienced 30 min of warm ischemia, when compared with simple cold storage. Further studies need to be conducted, but this study suggests that machine perfusion preservation has the potential to reclaim and preserve liver tissues after warm ischemic insult.

Over the past century, the concept of interfering with the immune response at various sites by blocking the formation, stimulation, proliferation, and differentiation of lymphocytes has led to relentless development of new immunosuppressive drugs. These agents are associated with reduced risk of short- and long-term toxicity and have dramatically improved allograft and patient survival, especially in recipients of solid organ transplants. Current protocols in such patients are nearly all calcineurin-inhibitor based, using cyclosporine or tacrolimus, as part of dual, triple, or sequential therapy. This review focuses on agents currently in clinical use at transplant centers in United States. The drugs are described in terms of their basic mechanisms of action, therapeutic uses, clinical studies, and adverse effects. In addition, the efficacy and toxicity of a few promising new therapeutic approaches are examined. Finally, important challenges regarding pharmacological immunosuppression as it relates to solid organ and composite tissue allotransplantation are discussed.

Background: High-dose tacrolimus (FK506) monotherapy has significantly prolonged rat hindlimb allograft survival. With an eye toward direct clinical application, we used a large-animal extremity composite tissue allograft model to assess the antirejection efficacy and systemic toxicity of combination FK506-mycophenolate mofetil (MMF) treatment., Methods: Radial forelimb osteomyocutaneous flap transplants were performed between size-matched outbred pigs assigned to one of two groups: 5 control pigs received no immunosuppression and 9 animals received a once-daily oral FK506-MMF-prednisone regimen. Rejection was assessed by visual inspection of flap skin and was correlated with serial histopathologic examination of skin biopsy specimens., Results: In all control pigs the flap was completely rejected on day 7. Of the 9 pigs receiving treatment, 3 died from pneumonia on days 29, 30, and 83 without signs of rejection and another died from gastric rupture on day 42 with persistent mild rejection. The remaining 5 animals were free of rejection at the end of the 90-day follow-up period (P < 0.005 vs controls). Overall, 5 pigs had pneumonia, 4 septic arthritis, 3 toe abscesses, and 5 diarrhea and decreased weight gain., Conclusions: Combination oral FK506-MMF treatment provided a superior antirejection effect but more produced more toxicity than that previously demonstrated with cyclosporin A-MMF therapy in our model. Our results suggest that reduction of FK506 or MMF doses might decrease both infectious and drug-specific side effects while still providing adequate prophylaxis against rejection.

Background: The presentation of infection in immunocompromised patients can be subtle. Patients often undergo extensive testing and empiric treatment for rejection and infection while awaiting the results of the biopsy and culture results. Delay in diagnosis of either entity can result in a worse clinical outcome. Lysozyme activity has been found to be both a sensitive and a specific marker for infection in laboratory animals and trauma patients. Our goal was to determine whether lysozyme activity could serve as a reliable marker for infection in immunocompromised organ transplant recipients., Methods: Transplant recipients from three clinical categories were enrolled in this study. Group 1 (n = 16) were patients hospitalized for sepsis (culture-positive), and Group 2 (n = 13) for biopsy-proven rejection. Group 3 (n = 51) were recipients who had routine blood sampling in the clinic. In Groups 1 and 2, blood was collected within 24 h of hospital admission and centrifuged, and serum samples were stored at 80 degrees C until processing. Lysozyme activity was assayed by turbidimetric measurement on a sample of a standard suspension (0.15 mg/ml) of Micrococcus lysodeikticus in buffer using a spectrophotometer to read the optical density at 450 nm. The lysozyme activity level was then determined by the measuring activity at 1 min subtracted from activity at 4 min. White blood cell count was determined by using a flow cytometer. Statistical comparisons between groups were made using paired Student's t test., Results: Serum lysozyme was found to be significantly elevated in Group 1; the mean level of activity was 60.1 +/- 13 (P < 0.05) compared to the level of activity in Group 2, mean 41.1 +/- 11, and Group 3, mean 40.8 +/- 13. A level of 45 units of activity/ml of serum or above indicated infection and not rejection in the patients admitted to the hospital., Conclusions: These findings indicate that the lysozyme activity assay appears to be useful in differentiating infection from rejection in transplant recipients., (Copyright 1999 Academic Press.)

We report a case of a patient who developed type II diabetes after receiving a successful combined kidney and pancreas transplant for type I diabetes and end-stage renal disease. This patient underwent a combined kidney and pancreas transplant and had no evidence of rejection with good function following the transplant for nine months. The patient developed significant post-transplant obesity with her transplant weight of 80 kg rising to 109 kg. At this level of obesity, the patient developed fasting hyperglycemia of 180 mg/dl with no change in her renal function or her pancreas exocrine function. She developed hyperinsulinemia to this fasting hyperglycemia. The clinical course of this patient demonstrates that rapid weight gain following transplantation can result in type II diabetes.

The swine liver has been used for experimental transplantation and as an ex vivo support system for patients with fulminant hepatic failure. Preservation of liver function after the cold storage period can be accomplished by complying with several key steps during the procurement: Keep the procedure short, provide extensive exposure, allow only minimal dissection, irrigate the portal system through the splenic vein and thereby obtain regular blood flow through the organ up to the clamping point, and ice the liver abruptly in situ. This retrieval technique was used and evaluated in 10 pigs. The method allowed a short and successful organ procurement while preserving normal function of the liver ex vivo.

The waiting list for cadaver kidney transplantation continues to grow. Yet there has been little increase in the number of living-donor transplants. At many centers, willing relatives are turned down as potential donors because of poor HLA ABDR matching with the recipient. It has been our policy to accept the 0-haplotype-match (0-HTM) living-related donor. We studied long-term (6-year) outcome of 0-HTM transplants compared with the outcome of transplants from 1- and 2-HTM recipients and from cadaver donors. Since 1984, 352 adults have received primary living-related renal transplants, and had a minimum of 1 year of follow-up: 92 2-HTM, 216 1-HTM, and 44 0-HTM. In the same period and with the same follow-up, 362 adults have received primary cadaver (CAD) renal transplants. Immunosuppression consisted of cyclosporine, azathioprine, and prednisone (triple therapy) for living-donor and sequential therapy for CAD recipients. ABDR match (mean +/- SD) for 0 HTM was 1.3 +/- 8; CAD, 2.0 +/- 1.6; % peak panel-reactive antibodies (PRA) for 0 HTM was 1.2 +/- 5.3; 1 HTM, 6.7 +/- 20; 2 HTM, 7.5 +/- 21; CAD, 15.5 +/- 30. The percentage of PRA at the time of transplant for 0 HTM was .7 +/- 4.4; 1 HTM, 4.1 +/- 1.6; 2 HTM, 6 +/- 18; CAD, 7.2 +/- 20. While the number of ABDR matches was significantly fewer for 0 HTM than for the other groups, the % PRA at transplant and the peak % PRA were less in the 0-HTM group. Other demographics were not significantly different. Patient survival was significantly lower in the CAD group vs. 2-HTM recipients (P < .05). The living-related grafts had significantly greater survival than the CAD grafts (P < .05), but there was no significant difference between 0-, 1-, and 2-HTM graft survival. The most common causes of graft loss in all groups were death and chronic rejection. In our experience, the long-term graft survivals of 0-HTM and 1-HTM transplants are the same, and both are superior to CAD results, using 0-HTM living-related donor transplants should be continued and encouraged.